PROJECT SUMMARY Growing evidence suggests addiction and other diseases of behavioral control result from the development of maladaptive habits. Indeed, an overreliance on habit is associated with the compulsive phenotype found in patients diagnosed with addiction and alcoholism, and comorbid conditions including obsessive-compulsive disorder and schizophrenia. Addictive substances and stress are thought to hijack the brain systems that normally support habit learning, causing habits to form faster and more strongly influence behavior than normal. This results in behavior that is insensitive to its consequences, even when those consequences are negative. Our ultimate goal is to expose the epigenetic-genomic-physiological-functional conduit that allows stress and exposure to addictive substances to promote these maladaptive habits. To achieve this, our specific goal here is to expose the multi-layered biological architecture required for mechanistic understanding of adaptive and maladaptive habits. Thus, this work will provide insight into how pathological states arise and what can be done to combat them. The striatum has long been known to function in habit learning. Where information is lacking is on how each striatal projection pathway, the direct- and indirect-projections to basal ganglia output nuclei, contribute and how their function might differ depending on the anatomically and functionally distinct medial and lateral striatal subdivisions. We will use a multi-faceted and integrative approach to expose the physiological and molecular changes that occur in each striatal subcircuit during goal-directed and habit learning. Our preliminary investigations have indicated that one major epigenetic repressor, HDAC3, functions in the striatum as a negative regulator of habit formation. Our hypothesis is that dorsal striatal HDAC3 functions as a molecular gate over habit, being engaged at the promoters of key neuronal activity genes to slow the transition to habit and being removed when conditions are ripe for habits to dominate. Thus, chronic stress and exposure to addictive substances might open this gate, creating an epigenetic landscape that biases future behavioral strategy towards habit, even with this is not adaptive, producing the compulsivity that marks many mental illnesses. Our proposed research begins to test this by investigating the molecular and cellular mechanisms that allows HDAC3 to regulate habit. This will enable future investigations into how disruptions in these mechanisms promote maladaptive behavior.